Genetic, biochemical and neuropathological studies support the idea that cerebral elevation and accumulation of the amyloid beta-peptide (Ab) are early and necessary steps in the pathogenesis of Alzheimer's disease (AD). Abeta is produced by sequential proteolytic cleavages of the amyloid precursor protein (APP) by a set of membrane-bound proteases termed beta-and gamma-secretases. Heterogeneous gamma-secretase cleavage at the C-terminal end of Abeta produces two major isoforms of Abeta, Abeta40 and Abeta42. While Abeta40 is the predominant cleavage product, the less abundant, highly amyloidogenic Abeta42 is believed to be one of the key pathogenic agents in AD and increased cerebrocorical Abeta42 is closely related to synaptic/neuronal dysfunction associated with AD. Furthermore, mutations in the APP and presenilin genes that cause rare early-onset forms of familial Alzheimer's disease (FAD), universally lead to an increased production of Abeta42. Thus, agents which are able to selectively reduce Abeta42 production are attractive and promising as therapeutic reagents for treating AD. Our preliminary studies showed that several triterpene natural products (known as "ginsenosides") derived from heat-processed ginseng (e.g. red ginseng), selectively lower the production of Abeta42. Based on this key preliminary data, the major goal of this proposal is to investigate the mechanistic basis of anti-amyloid (e.g. Abeta42-reducing) activity of these ginsenosides and other related natural products, and to evaluate their therapeutic potential using in vitro and in vivo models of (AD). To address these issues, we will carry out the following Specific Aims: (1) To investigate the mechanism of the anti-amyloid activity of selected ginsenosides; (2) To investigate the effects of Abeta42-lowering ginsenosides on Alzheimer-like pathology in a mouse model of AD; (3) To test the effects of Abeta42-lowering ginsenosides on neuronal dysfunction in a mouse model of AD: parallel analyses using fMRI, electrophysiology and behavioral approaches. Since these Abeta42-reducing ginsenosides can directly antagonize the key pathological event in AD, successful completion of our studies will help determine the therapeutic benefit of ginsenosides in AD.